Para-aminobenzamides, acid addition salts thereof, and their production



Patented Dec. 13, 1949 PABA-AMINOBENZAIVIIDES, ACID ADDITION SALTS THEREOF, AND THEIR PRODUCTION Raymond 0. Clinton, Glendale, Calif., and Ches- OFFICE ter Merle Suter, Albany, N. Y., assignors to Sterling Drug Inc., Wilmington, Del., a corporation of Delaware No Drawing. Application May 27, 1947, Serial No. 750,888

14 Claims. 7 1 This invention relates to p-aminobenzamides, and salts thereof, wherein the amide nitrogen atom bears an alkamine substituent containing sulfur or oxygen, and to processes for preparing the same. It more particularly relates to N-tertiary aminoalkylmercaptoalkyl p-aminobenzamides and N tertiary amino alkoxyalkyl-paminobenzamides and nitrogen-alkylated derivatives thereof, and water-soluble salts of the same. Compounds of the above type have hitherto been unknown. We have discovered that they have valuable pharmacological properties. In particular these compounds are good local anesthetics, being in general distinguished by their efiective pharmaoodynamic qualities and their freedom from undesirable toxic manifestations and untoward reactions.

Among the compounds which comprise our invention are those which have the general formula wherein R and R represent hydrogen or lower N 2 (2-ethylmethylaminoethylmercapto)-1- methylethyl-p-amino-benzamide of the formula:

N -2- (2-N-pyrrolidinopropylmercapto) ethyl-pethylaminobenzamide of the formula:

cmmnG-o O-NH-(CHzhSCHaCH(CHa)NC4Ha N methyl-N-3- (2-butylethylaminopropylmercapto)propyl-p-n-buty1aminobenzamide of the formula:

In any of the above compounds the sulfur atom may be replaced by oxygen.

The R and R groups are lower alkyl radicals, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and amyl or hydrogen. Both R. and R can be hydrogen, the same or different alkyl radi- -cals, or one can be hydrogen and the other an alkyl radical. A and A represent lower alkylene radicals of two to five carbon atoms such as ethylene, trimethylene, tetramethylene, pentamethylene, 1,2-propylene, 1,2-buty1ene, 2,3-butylene and the like. The S (or O) linkage may be to one terminal position of the alkylene chain and the amino group may be linked to the other terminal position, or either or both types of substituents may be at intermediate positions on the alkylene chain. The grouping, B, represents a tertiary amino group of the following types: dialkylamino groups which may be expressed as NR"R." wherein the alkyl radicals R" and R' vary from methyl through amyl and include both straight and branched-chains; aliphatic heterocyclic amino groups which may be expressed as N=R."" wherein R."" represents a divalent radical which, together with N, forms a cyclic tertiary amino radical such as the morpholino, piperidino, pyrrolidino, Z-methylpiperidino, 4-methylpiperidino, 2,6-dimethylpiperidino, piperazino and related aliphatic-type tertiary amino groups. These amino groups are all derived from secondary organic amines which are aliphatic in character. That is, they are derived from strong secondary amines, having ionization constants in the range of 1 10- to IX 10. They all behave chemically in a similar manner which is related to the chemical behavior of the simple dialkylamines such as diethylamine.

The compounds to which our invention relates can be prepared by reacting an oxygenor sulfurcontaining amine having theformula wherein R, A, A, Z, and B have the significance C4H9NH Ha)-( :)3S CH2 s) :Hs) (C4110) N (3 (2 dibutylaminoethylmercapto) 2 I methylpropyl)-p-amino-benzamide of the formula:

given hereinabove, with a p-nitrobenzoyl halide to form a p-nitrobenzamide of the type i U and subsequently reducing the nitro group to an amino group, the resulting compound having the formula RI The sulfur-containing amines may be synthesized by reacting in the cold an aminoalkanethiob of the formula BA'-ZH and a haloalkylamine m hydrohalide, XANHR'. H -X,}; where 'X represents a reactive halogen (Cfi-JfiApc. 8., 65,458 (1943); 67, 59% (1945)). Representative of this synthesis is the preparation oi--2-(-2-diethylam inoethylmercapto)diethylamine from 2-diethyl'-- drobromide:

The oxygen-containing amines of the type NI-Iz (CHzQsO- A' -B may be obtained-by .the-reaction of an amino alcohol,- E-A-- -OH-,-with acrylonitrile and. subsequent reduction of the product (J. A. cps" 66, 725 (19 14)). The follow- 7 Among the-chemical reducing agents that are suitable are iron and hydrochloric; acid; -ferrous sulfate and ammonia; tin and-hydrochloric acid. The nitro group of p nitrobenzamides of'oxygeninterrupted amines of thetype uoicsn'rc'oif a O A-"+1;-

can be reduced chemically bythe abovdmethods or can be cataly tically hydrogenated-tome' cor responding p aminobenzam'ides. lysts for this-procedure include Raneya nickel, platinumox-ide and palladium:blaek.=-=

The p-aminobenzamides' which comprise our invention may also be synthesized by the following' proceduresr A lower alkyl p-nitrobenzoate isareacted with'an oxygenor sulfur containing amine of the type NHRA--ZA' -B according-zto the equation:

-xolcfinlooolur HII\IA-Z'A'LB Alk represents an alkyl group and R, A, Z, A 70 of is condensed with an amine of the formula 75 Suitable cata 55 NHR'AZ-A'-B as shown by the following equation:

p-NHaCsHaCOOAlk HNAZA'B p-NH CaH 4GONI-AZA-B AlkOH A p-acylaminobenzoyl halide is reacted with an amine of the formula NHR'-AZ-A--B as follows? p-Ay1 Nacu-1;cox"+ HN-A-ZA'B aminoethanethiol and 2-bromodiethylamine hywherein-Acyi-"repiesents a simple acyl group such aslaetyl, benzoyl or the like, X represents halogen;-and-R', A, Z, A, and B have the meanings given hereinabove. The acyl group is subsequently-removedby partial hydrolysis- If the acylradical is a carb'obenzoxy group,

it may be removed byifcatalytic 01' chemical re duction; as with platinum catalysts "01" jwithso dium'inliquidarriindnia.

The N substituted ami'riobenzamiues which bear an 'alkyl substituent," R; on thep amino group may be prepared by a variety" of methods. In our preferred procedure; the alkyr roup'is introduced into theN-sub stit'uted pl afnin'obenza- Iriid by reductive alkylatidn'of an acuve carbonyl compound '(viz'. an" ameh'yae of ket'one'). An illustration is "the introdiitionbi apropyl group by treating the p -arninbberizamide With' propionaldehyde in a reducing medium.

Another satisfactory method is -to' introduce the alkyl group directly byalkylat-ion with alkylating agents such as methyl and-ethyl sulfates,-methyl and=ethyliodides and'otherlower alkyl halides (for example,- the propyl,-.butyl-andamyl chlorides, bromides and iodides). The desired monoalkylderivatives may be' separated from the dialkyl compounds by conversion to the acid-insoluble N nitro'sd compoundsand subsequent T regeneration of the monoaikyl product "by treatment with acid. In similar ways, the alkyl group may first be introduced with p a'm-inobenzoic acid or an ester thereof and the latter canthen be converted mu;- p airyiemmesszemmes by the methods shown-herein:

The tertiary aminoalkylmereapto'alkyl paniihebenzarifius andtertiary aniinoalkoxyalkylp-aminobenzamides are moderately' strong organiofbasesjf Thjeyare's'oluble in organic solvents, only 'siightly solublein' waiter afidsoluble'in dilute aqueous acids. They are convertible into'watersoluble, neutra1 or weakly acidic-saltswith the commonbrganie and inorganic acids, the anions ofwhich are innocuous upon oraLparenteral or topical aol'ininis't'ra'tion'. These: acids include hydrochloric, hydrobroniic, hydriodic, sulfuric, sulfamic, phosphoric, tartaric, citric, boric, lactic, acetic and -the like.;

The followin examples illustrate thecomthen extracted with ethyl acetate.

Example 1 A. N -2- (2-diethylaminoethylmercapto) ethyl-pm'trobenzamicle.To a stirred solution of 37.8 g.

' of sodium bicarbonate and 52.8 g. of 2-(2-diethylaminoethylmercapto)ethylamine in 240 cc, of

water is added at room temperature during 1 hour a solution of 66.9 g. of p-nitrobenzoyl chloride in 600 cc. of dry chloroform. After an additional hour of stirring the chloroform layer is separated and the water layer extracted with an additional 50 cc. of chloroform. The com- :bined chloroform extracts are washed with water, with dilute sodium bicarbonate solution or dilute alkali, and then with water, and finally dried with anhydrous calcium sulfate. Removal of the solvent by evaporation in vacuo leaves a pale yellow,

oily residue of the amide in high yield.

B. N -2- (2-diethylaminoethylmercapto) ethyl-p- 'aminobenzamzde.-A solution of 255 g. of ferrous sulfate heptahydrate in 900 cc. of water is heated to 80-85 C. and agitated vigorously. To it are added dropwise in 45 minutes a solution of 42.5 g. of N-2- (2-diethylaminoethylmercapto) ethyl-pnitrobenzamide in 320 cc. of alcohol, and a solution of 135 cc. of 28% ammonium hydroxide in 150 cc. of water. The additions are maintained at such rates that the reaction mixture is always basic. After addition the mixture is agitated at 80-85 C. for an hour, the volume being maintained by the occasional addition of alcohol. The mass is filtered with a filter aid such as Filtercel and the filtrate is evaporated in vacuo until the alcohol is removed. The aqueous residue is made strongly alkaline with ammonium hydroxide and then extracted with ethyl acetate. The extracts are dried with anhydrous calcium sulfate and evaporated under reduced pressure (0.05 mm. at 60 C.) N-2- (2-diethylaminoethylmercapto) ethyl-p-aminobenzamide is obtained in 77% yield. Up'on crystallization from a mixture of ethyl acetate and hexane it forms small white prisms melting at 70-7l 0. Its dipicrate forms bright yellow-orange needles melting at 132.5-l35 C.

The reduction can also be carried out by the following procedure: A mixture of 45.6 g. of the 'p-nitrobenzamide (Example 1A), 200 cc. of 50% aqueous alcohol and 11.9 cc. of concentrated hydrochloric acid is stirred and refluxed. To it is added in small portions 47.3 g. of reduced iron. After the addition the mixture is stirred and refluxed for 2 hours longer. The mass is filtered and the filter cake is washed with hot alcohol. The filtrate is evaporated under reduced pressure until the alcohol is removed. The aqueous residue is made basic with concentrated ammonia and The ethyl acetate solutions are dried with anhydrous potassium carbonate, filtered and evaporated in vacuo. The residue of N-2-(2-diethylaminoethylmercapto(ethyl-p-aminobenzamide is crystallized from a mixture of ethyl acetate and hexane and melts at 69-70 C.

' C. N -2- (2-diethylaminoethylmercapto) ethyl-paminobenzamide dihydrochloride.The amide for Example 13 is dissolved in isopropyl alcohol. To this solution is added an excess of concentrated hydrochloric acid. The mixture is chilled and allowed to stand in the cold, whereupon white crystals of the hydrochloride are deposited. Re-

crystallization from isopropyl alcohol gives tiny, white prisms of the dihydrochloride, M. P 172.5-

1 filter cake washed with hot benzene.

6 174 C. It is readily soluble in water and has the structural formula I Y Example 2 N -2- (2-diethylaminoethylmercapto) ethyZ-p-n butyZaminobenzamida-A mixture of 59 g. of N-2- (2-diethylaminoethylmercapto) ethyl p aminobenzamide, 52.2 g. of pure zinc dust, 49.2 cc. of glacial acetic acid and 200 cc. of dry benzene is stirred and refluxed. To this mixture is added dropwise in minutes a solution of 17.4 g. of n-butyraldehyde in 20 cc. of dry benzene. After addition the mixture is stirred and refluxed an additional hour. It is filtered while hot and the The filtrate (two layers) is made strongly alkaline with sodium hydroxide solution and the benzene layer for 3 hours).

is separated. ,The aqueous layer is extracted twice with benzene. The combined benzene extracts are dried, decolorized with charcoal and evaporated under pressure (0.05 mm. at 60 C.

N-2- (2-diethylaminoethylmercapto)ethyl-p-mbutylaminobenzamide is a viscous yellow oil. It has the structural formula It forms a dipicrate which crystallizes from glacial acetic acid as small, yellow-orange prisms, M. P. Pia-149 C.

When in the above example, propionaldehyde is used instead of butyraldehyde, there is obtained Example 3 4 to) ethyl-p-nitrobenzamide.--2- (2 -diethylaminoethylmercapto)diethylamine is reacted with pnitrobenzoyl-chloride at room temperature as disclosed in Example 1A. The resulting N-ethyl-N- 2-(2 -diethylaminoethylmercapto) ethylp -nitrobenzamide is a light oil. It forms a crystalline chloroplatinate of M. P. 154-155 C. (dec.).

C. N -ethyZ-N- 2 -(2 diethylaminoethylmercapto) ethyl-p-aminobenzamide is obtained by the reduction of the corresponding p-nitrobenzamide (Example 3B) with ferrous sulfate and ammonia by the procedure of Example 1B. It is a light colored oil which forms a crystalline dipicrate of M. P. 133-1335 C. It has the structural formula Example 4 A. Dimethylaminoethylmercaptoethylamine is prepared by reacting 0.5 mole of 2-bromoethy1- amine hydrobromide with 0.5 mole of z-dimethylaminoethanethiol in the presence of 1 ,mole of sodium-ethoxide in absolute ethanol at -10 C.

It distils at 53 C. (0.04 mm.) 71.13 1.4660.

C. N 2 (2 N morpholinylethylmercapto) ethyZ-p-aminobenzamide is isolated as a yellow oil after the reduction of the corresponding p-nitrobenzamide (Example 10B) with ferrous sulfate and ammonia (see Example 1B). It has the following structural formula CHiCHz Example 11 A. N 3 (3 diethylaminopropylmercapto)- propyZ-p-nitrobenzamide is synthesized from 3 (3 diethylaminopropylmercapto) propylamine (B. P. 86-87" C. (0.04 mm); n 1.4880; prepared from 3-diethylaminopropanethiol and 3-bromopropylphthalimide) and p-nitrobenzoyl chloride, according to the method shown in Example 1A. The product is a light yellow oil which forms a crystalline picrate of M. P. 102.5-105 C.

B. N 3 (3 dzethylaminopropylmercapto)- propyl-p-aminobenzamide is prepared by the reduction of the corresponding p-nitrobenzamide (Example 11A) according to the procedure of Example lB, using ferrous sulfate and ammonia. It is a light yellow oil, a sample of which on analysis was found to contain 4.17% N and 9.51% S (the calculated values are 4.33% N and 9.89% S). It has the structural formula nmQ-c ONH(CHz)3 s (CHahN (C2115)? Example 12 A. 2 (2 diethylamz'noethoxy) ethyZamine.-A

solution of 1 mole of 2-chloroethyl 2-phthalimidoethyl ether with 3 moles of diethylamine in 1500 cc. of alcohol is refluxed for 30 hours and then evaporated in vacuo to dryness. The residue is taken up in water and extracted with three 200-cc. portions of ether. The ether solution is evaporated and the resulting 2-(2-phthalimidoethoxy) ethylamine is cleaved with hydrazine hydrate (Ing and Manske, J. Chem. Soc., 2348 (1926) 2-(2-diethylaminoethoxy) ethylamine distils at 78 C. (4 mm.) n 1.4430.

B. N Z-(Z-dzethylaminoethoxy)ethyZ-p-nitrobenzamide.-One mole of 2 (2 diethylaminoethoxy)ethylamine in an aqueous solution of a 1.5 moles of sodium bicarbonate is treated with a 1.2 moles of p-nitrobenzoyl chloride in chloroform, as in Example 1A. From the chloroform layer, after washing with dilute bicarbonate solution and evaporation, is obtained N-2-(2-diethyl aminoethoxy) ethyl-p-nitrobenzamide, melting at 515-52 C. and forming a fiavionate of M. P. 190.5-192 C. Y

' C. N 2 (2 diethylamz'noethoxy(ethyl paminobenzamide is prepared from the corresponding p-nitrobenzamide (Example 123) by reduction with ferrous sulfate and ammonia, according to the directions given in Example 1B. It

10 forms white crystals which melt It has the formula NH2C oNmcHmo cmnmomm D. N 2 (2 diethylaminoethoxwethyl pamz'nobenzamide dihydrochloride.-The base (Example 12C) is taken up in isopropyl alcohol and treated with excess dry ethereal hydrogen chloride. The precipitated dihydrochloride may be crystallized from isopropyl alcohol or from a mixture of alcohol and ethyl acetate, and melts at 177-179" C. The crystalline dihydrochloride is easily soluble in water.

Example 13 A. N -3- (z-dz'ethylaminoethozcy) propyZ-p-m'tro- Q benzamide is obtained by reacting p-nitrobenzo yl" chloride with 3- (Z-diethylaminoethoxy) propylamine according to the procedure of Example 12B. It is a light yellow oil which forms a picrate of M. P. 113.5-114.8 C.

B. N-3- (Z-diethylaminoethoxy) propyl-p-aminobeneamide is prepared by reducing the corresponding p-nitrobenzamide (Example 13A) with ferrous sulfate in ammoniacal solution, as disclosed in Example 1B. It is isolated as a lightcolored oil which forms a water soluble citrate of M. P. 111l11.5 C. Its structural formula is Example 14 A. N-3-(3-diethylaminopropoary) propyl p-ni trobenzamide is synthesized by the reaction of p-nitrobenzoyl chloride on 3-(3-diethylamin'opropoxy) propylamine by the general method disclosed in Example 12B. It is a light-colored oil which forms a picrate which melts at 94.5-95.5 C.

B. N .3 (3 diethylamz'nopropoxy)propyl p aminobenzamide is obtained from the corresponding p-nitrobenzamide (Example 14A) by reduction according to the procedure of Example 13. It is a light-colored oil and a sample was found to contain 4.56% N (calculated, 4.56% N). It has the structural formula Example 15 N -ethyl N -2-(2-diethylaminoethylmercapto) ethyl-p-n-amylaminobenzamide is prepared by reductively amylating 1 mole of N-ethy1-N-2-(2- diethylaminoethylmercapto)ethyl-p-aminobenz amide (Example 3C) by refluxing with 4 moles of zinc dust and 4.1 moles of glacial acetic acid in dry benzene while 1.2 moles of n-valeraldehyde in dry benzene is added, according to the method of Example 2. The desired amide is separated in the benzene layer after filtration and alkalization of the reaction mixture. It is isolated from the purified benzene solution by evaporation and has the structural formula What we claim is: 1. A compound having the formula RNHQC ONAZ-AB wherein R and R represent members of the group 5 consisting f hydr gen and loweralkyl radicals,

at 67.568.5 C;

A-and- A are lower alkylene radicals; Zis'a'mem- 1 her of the group consisting of O and S, and Hisa dialkylamino group, in which thealkyl groups attached to'the amino group'may be joined to form a heterocyclic radical of the group consisting of piperidines, morpholines, pyrrolidines and piperazines, and Water-soluble acid-addition salts thereof.

2. A compound having the formula wherein R and R represent members of the group consisting of hydrogen and lower alkyl radicals, A and A are lower'alkylene radicals and B is a dialkylamino' group, in which the alkyl groups attached to -the-amino: group may be joined to form-a: heterocyclic radical of the group consistingqofzpiperidines, morpholines, pyrrolidines and Diperazines, and water-solubleacid-addition salts thereof.

3.: A compound: havingitheiformula" 4: A" tertiary aminoalk'ylmercaptoalkyl.- p aminobenzamide having the formula wherein A and A. represent lower alkylene radicals'and B represents; a dialkylamino-group, in.

which the alkyl groups attached to theamino group may be'joined' to form a heterocyclicradical of'the group consisting'of piperidines, mor pholines, pyrrolidines and piperazines, andzits water-soluble aoid-additi'onsalts.

5. A tertiary aminoalkoxyalkyl-p-aminobenzamide havingthe formula wherein A and A5 represent lower. alkylene radicals and B represents a dialkylamino group; in which the alkyl groups attached to the amino group may be joined to form a heterocyclic radical'of the group consisting of piperidines, morpholines, pyrrolidines and piperazines, and its water-soluble acid-addition salts.

6. A tertiary aminoalkylmercaptoalkyl pi-aminobenzamide having the formula NEQC onnzonczszonana wherein a: and y are integers from 2 to 5 and B is a dialkylamino group, inwhich the alkylgroups attached to the amino group may be joined to form a heterocyclic radical of the group consisting of piperidines, morpholines,.pyrr.olidines and piperazines; andn-itsswater-solume arid-addition salts.

'7. A tertiary aminoalkoxyalkyl-p-aminobenzamide having the formula 12 whereinrr-andyare'integersfrom-2 to SandB isa dialkylamino group; inwhlch -the alkyI-groupsattached totheamino group may be joined to form a heterocyclic radical'of 'the'group consistm ing' of plperidines, morpholines, pyrrolidines and piperazines, and itswater-soluble acid-addition" salts.

8. A dialkylaminoalkylmercaptoalkyl-p -amin0- benzamide having the formula wherein a: and y are integers from 2 to -5and Rf" and R arelower alkyl radicals, and its water=- soluble acid-addition salts.

9. A heterocyclic aminoalkylmercaptoalkyl*p aminobenzamide having theformula wherein a: and y are integers from 2 to 5 and-R""" is a divalent radical which, together with N, forms a cyclic tertiary-amino radical being selected from the group consisting-of piperidines; morpholines,

pyrrolidines and piperazines; and its water=- soluble acid-addition salts;

l0. N-2-(2 diethylaminoethylmercapto) ethyl p-aminobenzamide, having the formula NHzQ- onmcnmswmwwmm and its water-soluble acid-addition salts.

l1. N-2- (2-N-piperidylethylmercapto) ethyl-p amino-benzamide, having the formula on, onions and its Water soluble acid-addition 'salts.

12. In a process for-preparing a oompound'of the formula RI wherein R represents a member of the group consisting of hydrogen and lower'alkyl radicals, A and A are lower alkylene radi-cals, Z is a mem-- ber of the group consisting of O and S; and Bis a dialkylamino group, in which the alkyl groups attached to the amino group may be joined to form a heterocyclic radical of the group consist ing of piperidines, morpholines, pyrrolidinesand piperazines, the step which comprises chemically reducing'withl ferrous sulfate and ammonia/the; nitro group of. a,.p.-nitrobenzamide having the; formula by heating'a mixture'of saidlreaotants.

13. In a process-for preparing N-2-(2I-dlethy1s aminoethylmercapto) ethylm-p aminobenzamide,' having the formula;

NHQQoumonmsicflanmcmm the step which comprises chemically reducing with ferrous sulfate and ammonia the nitro group of the corresponding N-2-(2-diethylaminoethyl mercapto) ethyl-p-nitrobenzamide by heating a mixture of said reactants."

' 14'. In a. processfor preparing N --2"- (2' -N-"- NHQ-C ONH(CHz)2S(CHa):N

CHaC

the step which comprises chemically reducing with ferrous sulfate and ammonia the nitro group of the corresponding N-2-(2-N-piperidylethylmercapto)ethyl-p-nitrobenzamide by heat- CHzCH;

a. mixture of said reactants.

RAYMOND O. CLINTON. ff; CHESTER MERLE SUTER.

REFERENCES CITED The following references are of record in the me 01:: this patent:

UNITED STATES PATENTS Number Name 7 v Date Eisleb Mar. 9, 1937 Orthner et a1 June 29, 1943 Certificate of Correction Patent No. 2,490,780 December 13, 1949 RAYMOND O. CLINTON ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 3, line 67, for that portion of the equation reading CON -O-Z read OON-A-Z; column 8, line 6, for dipictrate read de'picrate; line 56, for that portion of the formula reading NH read NH column 10, line 29, for M. P. l11111.5 C. read M. P. 111113.5 0.;

and that the said Letters Patent should be read With these corrections therein that the same may conform to the recordof the case in the Patent Ofiice.

Signed and sealed this 4th day of April, A, D. 1950.

THOMAS F. MURPHY,

Assistant Uommz'ssz'oner of Patents. 

